Research Topic 11. Interventions. Reduced insulin/IGF-I signaling is implicated in the extended life span of several mammalian models, including calorie restricted rodents and dwarf mutant mice. Serum insulin and IGF-I levels are markedly reduced and insulin sensitivity for glucose disposal is increased in these models. Mice homozygous for the null mutation of protein tyrosine phosphatase 1B (PTP-1B -/-) closely mimic the insulin/IGF-1 phenotype of calorie restricted and dwarf mice. In addition, they exhibit reduced visceral adiposity, which may be an important mediator of these anti-aging effects, if this metabolic constellation of changes is important in murine longevity, the PTP-1B-/- mouse would seem promising as a new single-gene mutant model of extended longevity. The goal of this proposal is to determine if the PTP-1B-/- mouse is likely to be a longevity mutant, and thus provide the basis for obtaining R01 funding to establish definitively its longevity and healthspan and probe the underlying mechanisms. The Specific Aims are to determine if the PTP-1B -/- mouse: 1. Has an extended median lifespan and exhibits delayed/attenuated age-related pathology. 2. Exhibits reduced cell proliferation and/or inflammatory processes which are hypothesized to contribute to age-related disease and dysfunction. 3. Maintains its insulin/IGF-I/metabolic phenotype throughout adult life. If the results of most or all of these studies are affirmative, they will indicate that nullifying the PTP-1B gene is a genetic intervention with strong potential for retarding aging. These data would enable a R01 application to determine the effect of this genetic intervention on maximal longevity and aging, and to probe its underlying mechanisms. A PTP-1B-/- longevity mutant would also provide a new target for pharmacologic interventions to retard aging.